Disorders of lipid metabolism are responsible for several important established risk factors for cardiovascular disease, which continues to be the leading cause of morbidity and mortality in the United States. Despite of decades of research, many aspects of lipid metabolism are incompletely understood. Proprotein convertases (PCs) were suspected to be involved in lipid metabolism, but their importance has not been fully appreciated until the recent discoveries that two PCs were found to be associated with lipid disorders in humans. The mechanisms by which PCs influence cholesterol metabolism remain unclear. Our long-term goal is to delineate how PCs cleave substrates and regulate lipid metabolism. In this project, we will focus on how PCs influence lipid metabolism through angiopoietin-like 3 (ANGPTL3). This will be accomplished by conducting experiments addressing three Specific Aims. Specific Aim 1, in cell culture to examine how PCs influence the cellular processing of ANGPTL3 by using different compounds. Specific Aim 2, in a cell-free system to find out whether the interference of ANGPTL3 processing by PCs has any effects on activity of an enzyme named lipoprotein lipase, then to further examine in mice whether it also affects plasma lipid levels and formation of atherosclerosis in an atherogenic mouse model. Specific Aim 3: The physiological relevance of this biological event will be examined under different nutritional states and acute inflammation in mice. This study will be not only important to better understand the biologic processing of ANGPTL3, but also to delineate how PCs regulate lipid metabolism, ultimately, provides information that could lead to the development of potential novel approaches for regulating lipoprotein metabolism and preventing cardiovascular diseases.